D. A.

Evans

Pericyclic Reactions: Part4

Chem 206

! Other Reading Material:

http://www.courses.fas.harvard.edu/colgsas/1063

[3,3] Sigmatropic Rearrangements

Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 5,
Chapter 7.1: (Cope, oxy-Cope, Anionic oxy-Cope)
Chapter 7.2, Claisen

Chemistry 206
Advanced Organic Chemistry

S. J. Rhoades, Organic Reactions 1974, 22, 1 (Cope, Claisen)

S. R. Wilson, Organic Reactions 1993, 43, 93 (oxy-Cope)

Lecture Number 14

T. S. Ho, Tandem Organic Reactions 1992, Chapter 12 (Cope, Claisen)

Pericyclic Reactions4
! [3,3] Sigmatropic Rearrangements: Introduction
! Cope Rearrangements & Variants
! Claisen Rearrangements & Variants

Paquette, L. A. (1990). Stereocontrolled construction of complex cyclic

ketones by oxy-Cope rearrangement. Angew. Chem., Int. Ed. Engl. 29: 609.

! Problems of the Day:

Predict the stereochemical outcome of this Claisen rearrangement
Et

! Reading Assignment for week:

Et
O

Carey & Sundberg: Part A; Chapter 11

Concerted Pericyclic Reactions
K. Houk, Transition Structures of Hydrocarbon Pericyclic Rxns
Angew Chem. Int. Ed. Engl. 1992, 31, 682-708

diastereoselection
>87:13

144 C, 6h

CMe3

CMe3
Ireland, JOC 1983, 48, 1829

K. Houk, Pericyclic Reaction Transition States: Passions & Punctilios, Accts.

Chem. Res. 1995, 28, 81-90
Angew Chem. Int. Ed. Engl. 1992, 31, 682-708

Provide a mechanism for the indicated fransformation

OH

O
Me

D. A. Evans

Friday,
October 20, 2006

Me

KH, ! THF
H3O+ quench

Me
H

Me

Schreiber, JACS 1984, 106, 4038

Database Problem number 117: Key words: Rearrangement + Claisen

In a recent article, MacMillan and Yoon (JACS 2001, 123, 2448) reported the complex rearrangement illustrated below.
R2N

O
R2N
Cl
Me

Me

several equiv

Me

Yb(OTf)3
CH2Cl2, R3N

R2N

NR2
Me

Me

diastereoselection >95:5

Part A. Provide a mechanism for this overall transformation. In answering this question, you should illustrate
those transition states where stereocenters are generated and where stereochemcal information is relayed.
Part B. From your answer in Part A, illustrate the stereochemical relationships in the diamide product A.

Database Problem number 195: Key words: Rearrangement + Claisen

Provide a mechanism for the indicated transformation that accounts for the observed stereochemical outcome
(JACS, 1984, 7643).
O
SAr
O
Cl
S
O
C O
Ar
Cl
H Cl Cl

D. A. Evans

Introduction to [3, 3]-Sigmatropic Rearrangements

Chem 206

General Reviews:
S. J. Rhoades, Organic Reactions 1974, 22, 1 (Cope, Claisen)
S. R. Wilson, Organic Reactions 1993, 43, 93 (oxy-Cope)
T. S. Ho, Tandem Organic Reactions 1992, Chapter 12 (Cope, Claisen)
Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 5,
Chapter 7.1: (Cope, oxy-Cope, Anionic oxy-Cope)
Chapter 7.2, Claisen

The CopeTransition States

Relative Energy !!G:

CHAIR

BOAT

+ 5.8 kcal/mol

CHAIR

BOAT

+ 5.3 kcal/mol

X & Z = C, O, N etc

Relative Energy !G:

The Boat and Chair geometries for these transition structures are well defined.
Cope Rearrangement, Ea = 33.5 kcal/mol

Claisen Rearrangement Ea = 30.6 kcal/mol

The Reaction Energetics Goldstein, JACS 1972, 94, 7147

The FMO Analysis (Fleming page 101)

Bring two allyl radicals together to access for a possible bonding interaction
between termini.

!G523 = 46.3
!G523 = 40.5

The nonbonding
allyl MO

!2
X

bonding
bonding

It is evident that synchronous bonding is possible in this rearrangement

Chem 206

The DoeringRoth Experiments

D. A. Evans

Doering/Roth Experiments: Tetrahedron 18, 67, (1962):

The Geometry of the transltion state (boat vs chair) can be analyzed via
the rearrangement of substituted 1,5-dienes:

The Results

favored

Me
Me

Me

Me

Me

Me

Threo isomer

Me

Results:
Threo isomer

Me
H less favored

Me
Me

Me

Me

trans-trans:
90%

Me

Me

Me

Me

Me
Me

H disfavored

Me

Me

cis-cis:
10%

Me

trans-cis:
< 1%

Me

Meso isomer

Me

! Measure product composition from rearrangement of each diene isomer

H

favored

Me

Me

trans-trans

Me
H

Me

Me

Predictions:
Threo isomer

H less favored
H
Me

Me

Predictions:
Meso isomer

trans-trans: 0.3%
H

trans-cis

Relative Energy !!G:

Me trans-trans
H

CHAIR

BOAT

+ 5.8 kcal/mol

CHAIR

BOAT

+ 5.3 kcal/mol

trans-cis

Me

Me disfavored

Me

Me

Me
H

disfavored

Me

favored

Me

cis-cis

Me
Me

!!G
~ 5.7 kcal/mol

The CopeTransition States

H
H

Me

trans-cis: 99.7%

Me

Me
Me

H disfavored

Me

favored

Me

H
H

Me

H
Results:
Meso isomer

Me

Me
Me

Relative Energy !G:

The Boat and Chair geometries for these transition structures are well defined.

D. A. Evans

Chem 206

StrainAccelerated Cope Rearrangements

Ring Strain can be employed to drive the Cope process:

! Ring extension via divinylcyclopropane rearrangement

O

Me

"quantitative"

5-20 C

90%

Me
1.5 equiv

Li

(PhS)Cu

H
120 C

Me

Me

Brown Chem. Commun. 1973, 319

O Me Me

heat
xylene

Me

Me
LDA

Me

Vogel Annalen 1958, 615, 1

MeI

(EtO)2P

Me Me

Me
Li

60 C

Reese Chem. Commun. 1970, 1519

equilibrium stongly favors this isomer

O Me Me

Me

LDA

Me

OMe Me

Me

(EtO)2PCl

Me

Me

Piers, Can J. Chem. 1983, 61, 1226, 1239

! Position of Equilibrium dictated by ring strain issues:

20 C

(Ph3)3RhCl

EtNH2/THF

!-himachalene

Ring Strain can be employed to drive the Cope process:

H2

H
Vogel Angew. Chem. Int. Ed.
1963, 2, 739
favored

W. von E. Doering's Bullvalene

!

H
H
Wharton J. Org. Chem.
1973, 38, 4117
H

! However, tautomerism can shift the equilibrium:

H
keq ~ 10+5

220 C

Bullvalene: Ea = 13.9 kcal/mol

3h
OH

At 100 C one carbon is observed in nmr spectrum

Carey, Vol 1, page 630631

OH

90%

Marvell, Tet. Lett. 1970, 509

Energetically, how much does
tautomerization give you?

D. A. Evans

Documentation of Alkoxy Substituent Effect

Accelerated Cope Rearrangements

HO

Chem 206

The Anionic Oxy-Cope Rearrangement

HO

k1

HO

OX

OX
OX

k2
= 10 + 10
k1

k2

10 + 17

66 C
THF

10 +12 rate acceleration

A priori Estimate of the Acceleration (DAE)

pka (SM)
O

HO

Origin of the Rate Effect

pka (TS)
O

OH

1.2 hrs

OK

1.4 min

OK

11 hrs

O- +K

4.4 min

66 C

10 C

No Rxn

!!Gestimate = 15 kca mol -1

!!Gexperiment = 13 kca mol -1

HO

Effect probably comes from both

reactant destabilization
&
transition state stabilization

!GO = !GOH + 2.3RT [ pka TS pka SM]

O =

ONa

!GO
O

!G

no rxn

??

!G

(HMPT)

OLi

MeO

!GOH

!GO

(66 yrs)

XO

66 C
THF

HO

OH

OMe

Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 5,

Chapter 7.1: (Cope, oxy-Cope, Anionic oxy-Cope)
"Recent applications of anionic oxy-Cope rearrangements."
Paquette, L. A. Tetrahedron 1997, 53, 13971-14020

!GOH

MeO

Evans, Golob, JACS 1975, 97, 4765.

HO

Half-life

!GO = !GOH +

2.3RT [18 29] (in DMSO)

HO

"

" !

~ 15 kcal/mol

1.4 [ 11]

!GO = !GOH 15 kcal/mol at 298 K (in DMSO)

Maximal rates are observed under conditions where reactant is maximally destabilized

D. A. Evans

Chem 206

Anionic Substituent Effects: Bond Homolysis

Substituent Effects in Bond Homolysis

HO C CR3

DI

HO C

DI!I

+ CR3

O C

+ CR3

H
(H2O) pKa = 10.7

X
R

Ph

X
R

[1,3]

X Y

X Y

DI DII = 2.3 RT [pka (A) pka (B)]

HO C

[2,3]

ketyl

Acidities of these radicals are

HO C known in H2O, Hayon, Accts.
Chem. Res. 1974, 7, 114

[3,3]

A
O C CR3

Substituent Effects in Molecular Rearrangements

[1,2]

ene

HO C
Ph
pKa = 9.2

Y X

Y X

In DMSO, D = 2.3 RT [ 29 18] ~15 kcal/mol

Y X

! Substituent Effect based on ab initio calculations

(Evans, Goddard, JACS 1979, 101, 1994)

H
HO C H
H
BDE = 90.7
(BDE = 91.8 expt)

H
NaO C H
H
BDE = 80.6

KO C H

O C H

H
BDE = 79.0

H
BDE = 74.2

!D
+16.5 kcal/mol

Y X

C
C

C
X

X C

X C

RH

X C

X C

D. A. Evans
MeO

Chem 206

Anionic Oxy-Cope Rearrangement: Applications

OMe
MeO

OMe
O

NaH
OH

OMe
H
OMe

Me

H2C
H

Me

OH

OR

Jung, JACS 1978, 100, 4309

Jung, JACS 1980, 102, 2463

KH, THF

O Levine, JOC 1981, 46, 2199

KH

Me
ROH2C

OH

200 g from 75,000

virgin female cockroaches

Me

Me

Periplanone-B Synthesis

75%

MgX

Me

! THF

Me

ROH2C

Me

Still, JACS 1979, 101, 2493

OH
OR

KH

Me

OH

Me

KH, THF

Me

Me

Gadwood, JOC, 1982, 47, 2268

Me

Me

! THF
Me
Me

2 steps

Schreiber, JACS 1984, 106, 4038

Me
H

Synthesis of (+)-CP-263,114: Shair, JACS 2000, 122, 7424-7425.

O
HC CLi

50 C
OH

Me

Me

Me

O
CO2H
MeO2C

XMgO CH OR
2

H
Me

poitediol

Me

Me

H
Me

dactylol

Me

Me

Gadwood, JACS, 1986, 108, 6343

OMe

R
H

Me

Me

OH

OH

OH

Me

50 % yield

Me

OH

O
O

[3,3]
78!23 C

H
R

O
R

H
XMgO CH OR
2

R
H

53%

Dieckmann
CH2OR

Me

D. A. Evans

The Claisen Rearrangement

! General Reviews:

Chem 206

Recognition Pattern for Organic Synthesis: An Enforced SN2'

S. J. Rhoades, Organic Reactions 1974, 22, 1 (Cope, Claisen)

Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 5, Ch 7.2
Ziegler, Accts. Chem. Res. 1977, 10, 227 (Claisen)
Bennett, Synthesis 1977, 589 (Claisen)
Blechert, Synthesis 1989, 71 (HeteroCope)
R. K. Hill, Asymmetric Synthesis vol 3, Ch 8, p503 (chirality transfer)
Ziegler, Chem Rev. 1989, 89, 1423 (Claisen)

Claisen

SN2'

! The Reaction:

#H ~ 20 kcal mol-1

Stereochemical outcome is syn and controlled by hydroxyl stereocenter

R
1 O

There is good thermodynamic driving force for this reaction.

Bonds Broken: C-C! (65 kcal mol-1) & C-O" (85 kcal mol-1)
Bonds Made: C-O! (85 kcal mol-1) and C-C" (85 kcal mol-1)

X
2

X
O

! Themodynamics of Claisen Variants:

X

X=H
X = OH
X = NH2

1 O

!H (kcal mol-1)

Substituent

16
31
30

77%

~ 20

~ 20 kcal/mol

OH
H

180-200 oC

Rearrangements of Aryl Allyl Ethers: Traditional Applications

OR

Control of stereocenter 2 evolves into a decision how to

establish the hydroxyl-bearing stereocenter

~ 30

(Benson estimates)

Me

Me
Me 180-200 oC Me

Me
Me

OH

O
Cope Me

Me

Me

Me

~ 30 kcal/mol

OR

91%

Me
O

Heteroatom substitution at the indicated position increases

exothermicity as well as reaction rate

Me

65%

OH

Me

Me

E:Z = 6.7:1

The Claisen Rearrangement-2

D. A. Evans

Synthesis of Allyl Vinyl Ethers

! Endocyclic Olefins: Ireland, JOC 1983, 48, 1829

Et

Hg(OAc)2

OH

O
Et
144 C, 6h

OEt (solvent)

Watanabe, Conlon, JACS 1957, 79, 2828

Bronsted acids can also serve as catalysts

CMe3

R
B

Me3C
H

H2C

H2C

Cp2Ti

AlMe2

H
H2C

The Ireland approach to the bicyclic acid A:

X
Me

O
O
Me3C

Me

Me

HO

HO

Me

ratio 52:48
H

H
H

Me

OH
Me

Me

Me OH

Me

EtOCH=CH2

O
O

Me3C

Me3C

Me

Me

Me

OEt Me3C
H

OH

Me

X=H

HO

OEt

Me

Claisen

JOC 1962, 27, 1118

OEt

heat

96%

(review) S. H. Pines, Organic Reactions 1993, 43, 1

Me3C

! Exocyclic Olefins: House, JOC 1975, 40, 86

CMe3
O

Cl

heat

Ph

Use of Tebbe's Reagent: Evans, Grubbs, J. Am. Chem. Soc. 1980, 102, 3272.

Me3C
C

Ph

CH2

CMe3

CH2

For endocyclic olefins, overlap between developing sigma and pi bonds required. Best
overlap for forming chair geometry. As shown below, bring a radical up to either face
of the allylic radical. As the bond is formed, overlap must be maintained. Path A
evolves into a chair conformation while Path B evolved into a boat conformation.

75%

OEt

CH2

-EtOH

AcOHg

diastereoselection
>87:13

Me3C

Chem 206

ratio 75:25

for exoocyclic olefins, overlap between developing sigma and pi bonds is equally good
from either olefin diastereoface. In this instance, steric effects dominate & this system
shows a modest preference for "equatorial attack." A related case is provided below.

HH

Hg(OAc)2

HO
Me

Me

53% overall

HO
Me

Me

H !

O
H

The new stereocenter (!) introduced via the rearrangement had

the wrong configuration!

D. A. Evans

Claisen Rearrangement as vehicle for stereoselective olefin synthesis

Consider the following rearrangement:

Faulkner suggests that the installation of other substituents on Claisen

transition states will lead to enhanced reaction diastereoselection:

ke

ke

CHO
Me

O
Me

ka

Me

Me

!Ga - !Ge = 1.5 kcal/mol

Me

Me

CHO

Me

ka

#Note:

!!G = +1.5 kcal/mol

For R2 = Et

Me

Me

!G = +1.75 kcal/mol

They then suggest that there is a good correlation between cyclohexane "A-values" &
!!G for the rearrangement process. Their case is fortified by the following expamples:
CHO
110 C

R2

R1 (E)

R1

R2

Me
Me
Et

Et
iPr
Et

(E):(Z) found
90:10
93:07
90:10

O
X

R2

(Z)
a

Me

(E):(Z) found

H
Me
MeO

90:10
>99:1
>99:1

Me2N

>98:2

Faulkner, Tet Let 1969, 3243

Faulkner, JACS 1973, 95, 553
Johnson, JACS 1970, 92, 741

OY

Et

OPMB

Me
Et

CHO

R2

R1

(Z)

(E):(Z) predicted
91:9
94:6
91:9
Faulkner, JACS 1973, 95, 553

Me

R2
R1

Me

! Another comparison: (DAE) M. DiMare, Ph. D. Harvard University, 1988

The A-value of 2-methyl-tetrahydropyran is +2.86 kcal/mol (Lecture No. 6)

Me

(E)

R2

Me

The R2!X interaction should destabilize a as X gets progressively larger.

Faulkner & Perrin (Tet. Lett. 2783 (1969) have made the correlation between
!!G for rearrangement & !G for the corrresponding cyclohexane# equilibria:

R2

R2
110 C

R2

110 C

Me

Chem 206

The Claisen Rearrangement: Stereoselective Olefin Synthesis

OPMB
Et

procedure
Y = Ac, Ireland
Y = H, Johnson
Y = H, Eschenmoser

conditions

Me

LDA, TMSCl
HC(OMe)3, H+

TMSO
MeO

MeC(OMe)2NMe2

Me2N

T, C

(E):(Z) ratio

-78!+55
130
80

97:3
94:6
97.5:2.5